Edward's reign was marked by economic problems and social unrest that, in 1549, erupted into riot and rebellion. An expensive war with Scotland, at first successful, ended with military withdrawal from Scotland as well as Boulogne-sur-Mer in exchange for peace. The transformation of the Church into a recognisably Protestant body also occurred under Edward, who took great interest in religious matters. Although his father, Henry VIII, had severed the link between the Church of England and Rome, Henry VIII had never permitted the renunciation of Catholic doctrine or ceremony. It was during Edward's reign that Protestantism was established for the first time in England with reforms that included the abolition of clerical celibacy and the Mass and the imposition of compulsory services in English. The architect of these reforms was Thomas Cranmer, Archbishop of Canterbury, whose Book of Common Prayer is still used.

In February 1553, at age 15, Edward fell ill. When his sickness was discovered to be terminal, he and his Council drew up a "Devise for the Succession," attempting to prevent the country's return to Catholicism. Edward named his cousin, Lady Jane Grey, as his heir and excluded his half-sisters, Mary and Elizabeth. However, this decision was disputed following Edward's death, and Jane was deposed by Mary within 13 days. As queen, Mary reversed Edward's Protestant reforms, which nonetheless became the basis of the Elizabethan Religious Settlement of 1559.